Symptom severity and trajectories among adolescent and young adult patients with cancer

Abstract Background Patients with cancer experience significant symptom burden. We investigated symptom severity in adolescents and young adults (18- to 39-year-olds) during the year following a cancer diagnosis and made comparisons with older adult (those older than 40 years of age) patients with cancer. Methods All Albertan residents diagnosed with a first primary neoplasm at 18 years of age or older between April 1, 2018, and December 31, 2019, and who completed at least 1 electronic patient-reported outcome questionnaire were included. Symptom severity was assessed using the Edmonton Symptom Assessment System-revised. Descriptive statistics, multivariable logistic modeling, and mixed logistic regression modeling were used to describe symptom severity, identify risk factors, and assess symptom trajectories, respectively. Results In total, 473 and 322 adolescents and young adults completed a patient-reported outcomes questionnaire at diagnosis and 1 year after diagnosis, respectively. Adolescent and young adult patients with cancer reported high levels of tiredness, poor well-being, and anxiety. Important risk factors included metastatic disease, female sex, treatment types received, and age at diagnosis. Symptom severity varied by clinical tumor group, with those diagnosed with sarcoma having the worst scores for all symptoms at diagnosis and patients with intrathoracic or endocrine tumors having the worst scores for all symptoms at 1 year after diagnosis. Statistically significant differences in symptom severity over the 1-year period were observed between adolescents and young adults and older adults—specifically, the odds of having moderate to severe symptoms were statistically significantly greater among adolescents and young adults with respect to pain, tiredness, nausea, depression, anxiety, and poor well-being (all P < .01). Conclusions A substantial proportion of adolescents and young adults experience moderate to severe symptoms during the year following diagnosis. Modifying existing supportive services and developing interventions based on the needs of adolescent and young adult patients with cancer could aid symptom control.

Individuals diagnosed with cancer experience adverse symptoms as a result of their disease and its treatment.One systematic review of 21 multinational studies demonstrated that the following symptoms had a high prevalence across all cancer types: fatigue (59.6%), pain (48.0%), lack of appetite (45.4%), shortness of breath (43.7%), and nausea (40.1%) (1).Although prior studies have identified that symptoms vary by patient and cancer characteristics, adolescents and young adults (those 18 to 39 years of age) have largely been overlooked (1)(2)(3).This oversight is worrisome because adolescents and young adults with cancer often present with complex needs, given the unique challenges of their developmental stage, that may make them disproportionately at risk for high symptom burdens (4).Indeed, the existing literature has reported significantly higher levels of depression and anxiety as well as more concerns in the domains of "emotional, social, family, or spiritual," and "work or school" than older adults (those 40 years of age or older) (5).
Evaluating symptoms is crucial for informing future strategies to mitigate or prevent morbidity or to improve treatment compliance, with a goal of better quality of life (6,7).As a result, patientreported outcomes have been increasingly implemented across cancer centers as a way for clinical teams to collect direct input from patients on their well-being.Patient-reported outcomes are endorsed as a reliable mechanism to assess symptoms in a consistent manner and can lead to high-quality, patient-centered care (8,9).Though studies providing insight into patient-reported outcomes among adolescents and young adults with cancer do exist, there remains a paucity of research investigating trajectories and risk factors for high symptom burdens.Further, comparisons with older or younger cancer populations are warranted to truly understand the unique needs of this population.
Thus, we sought to address existing knowledge gaps by evaluating the well-being of adolescents and young adults diagnosed with cancer between the ages of 18 and 39 years in Alberta, Canada, through a retrospective cohort design using secondary patient-reported outcomes data.The objectives were to 1) comprehensively describe symptom severity among adolescents and young adults with cancer at diagnosis and 1 year after diagnosis and identify demographic and clinical risk factors for higher severity, 2) evaluate symptoms trajectories among adolescents and young adults with cancer during the year following diagnosis, and 3) compare symptom severity and trajectories with older adult patients with cancer.

Patient-reported outcomes in oncology in Alberta
The collection of patient-reported outcomes is the standard of care across the 17 ambulatory cancer centers in Alberta, with all patients treated at adult cancer centers routinely completing the Edmonton Symptom Assessment System-revised (ESAS-r) since 2014 (3,4,10).The ESAS-r is a valid and reliable patient-reported outcomes tool that assesses symptom severity for pain, tiredness, drowsiness, nausea, lack of appetite, shortness of breath, depression, anxiety, and overall well-being (11)(12)(13)(14)(15), where 0 represents the absence of symptoms and 10 represents the most severe symptoms.The ESAS-r has been used previously in cancer populations, including adolescents and young adults (5,16,17).For the purposes of this study, symptom severity was assessed continuously and dichotomously (0-3 ¼ no or low symptoms; 4-10 ¼ moderate to severe symptoms).

Study population
The Alberta Cancer Registry provided data on all Albertan residents diagnosed with a first primary neoplasm from 18 years of age onwards between April 1, 2018, and November 30, 2019, who were not diagnosed with multiple cancers, except nonmelanoma skin cancer, and completed at least 1 electronic patient-reported outcomes questionnaire.Adolescents and young adults were defined as individuals aged 18 to 39 years, and older adults were defined as those aged 40 years or older at diagnosis, respectively.This study was approved by the Health Research Ethics Board of Alberta-Cancer Committee (HREBA.CC-21-0004) and the requirement for consent was waived.

Statistical analyses
Bimonthly "windows" that created 60-day segments from the date of diagnosis to a maximum of 360 days were generated for each patient; the window corresponding to 0 to 60 days is referred to as diagnosis, and the window corresponding to 301 to 360 days is referred to as 1 year after diagnosis.When a patient completed multiple questionnaires within 1 window, we used the worst reported score for each symptom.
Frequencies, means, and standard deviations were used to describe the study population at diagnosis and 1 year after diagnosis by the following explanatory factors: sex, geographical zone of residence at diagnosis, metastatic status at diagnosis, crude treatment (ie, radiation therapy [RT] only, chemotherapy only, RT and chemotherapy, neither), Charlson Comorbidity Index score (18), cancer stage, and clinical tumor group (Supplementary Table 1, available online).To compare with older adults, 2-sample t testing or v 2 testing was used to assess differences in descriptive characteristics between age groups.We used logistic regression modeling to assess the relationships between the dichotomized symptom severity variable and explanatory factors both at diagnosis and at 1 year after diagnosis.Mixed logistic regression modeling with an unstructured covariance structure was used to assess changes in the odds of having moderate to severe symptoms over the year following diagnosis.All multivariable models were developed by including explanatory factors associated with the dichotomized symptom severity variable in the univariable model using a 2-sided P < .01 to account for the assessment of multiple comparisons.All analyses were undertaken using Stata, version 17, statistical software (StataCorp LLC, College Station, TX) (19).

Results
Of the 1787 adolescents and young adults with cancer who met our study inclusion criteria, 937 (52.4%) completed at least 1 patient-reported outcomes questionnaire in the year following diagnosis.
The proportion of adolescents and young adults with cancer reporting moderate to severe symptoms is shown in Figure 1 and Supplementary Table 2 (available online).In total, 53% of adolescents and young adults reported moderate to severe tiredness, followed by 50% reporting poor well-being, 41% reporting anxiety, and 34% reporting drowsiness.By tumor group, tiredness and poor well-being were among the top 3 symptoms for all groups (Figure 2).Notably, adolescents and young adults with sarcoma had the worst scores at diagnosis for all symptoms.
Identified risk factors for moderate to severe symptoms at diagnosis included metastatic disease for drowsiness (P ¼ .004)and female sex for anxiety (P ¼ .002)(Table 2).Metastatic disease was also a risk factor for poor appetite (odds ratio [OR] ¼ 2.7; 95% confidence interval [CI] ¼ 1.5 to 5.1; P ¼ .002)after adjusting for the Charlson Comorbidity Index score, as was treatment type for poor well-being (P ¼ .002)after adjusting for metastatic disease (Supplementary Table 3, available online).

Symptom severity at 1 year after diagnosis
In total, 322 adolescents and young adults completed a patientreported outcomes questionnaire at 1 year after diagnosis (Table 1).Nearly 60% of respondents were female, and the most common tumor groups were breast and hematologic, accounting for more than 50% of respondents when combined.Finally, the majority of patients resided in Calgary (50.0%), were diagnosed at stage I (26.4%), and were treated with chemotherapy and RT (41.9%).At 1 year after diagnosis, the ranking of symptoms by proportion of adolescents and young adults with moderate to severe severity was as follows: tiredness (39.3%), poor well-being (35.5%), anxiety (27.8%), depression (22.5%), pain (22.5%), drowsiness (21.9%), poor appetite (13.1%), and breathlessness (9.1%) (Figure 1; Supplementary Table 2, available online).Tiredness was the most important symptom for all tumor groups, except for patients with head and neck and intrathoracic tumors, where poor well-being was a greater concern (Figure 2).Notably, patients with intrathoracic tumors reported the greatest severity for all symptoms, except tiredness, where patients with endocrine cancers reported the worst symptoms.
Risk factors for moderate to severe symptoms at 1 year after diagnosis were identified only for pain, tiredness, drowsiness, and anxiety (Table 3; Supplementary Table 4, available online).For pain, the odds of having moderate to severe symptoms was statistically significantly greater if the patient received the diagnosis at an older age (OR ¼ 1.1; 95% CI ¼ 1.0 to 1.2; P ¼ .008),after adjusting for treatment types received.The odds of having moderate to severe tiredness was statistically significantly lower for male patients (OR ¼ 0.4; 95% CI ¼ 0.2 to 0.6; P < .001),and treatment types received was predictive of the odds of having moderate to severe drowsiness (P ¼ .009)and anxiety (P ¼ .004).

Symptom trajectories
Across all symptoms, the proportion of adolescents and young adults reporting moderate to severe symptoms decreased from diagnosis to 1 year after diagnosis (Figure 1).After adjustment (Table 4; Supplementary Table 5, available online), there were statistically significant improvements in severity for all symptoms over the year following diagnosis, except for pain (P ¼ .548).The largest improvements were observed for anxiety, poor wellbeing, tiredness, and drowsiness, with odds ratios below 0.8 (95% CI ¼ 0.7 to 0.8) and P < .001noted for all 4 categories.Finally, all    tumor groups in general observed improvements in symptom severity over the year following diagnosis, except patients with breast cancer, whose symptoms were relatively stable, and patients with endocrine and intrathoracic cancers, where symptoms appeared to worsen with time (Figure 2).

Comparison with older adults
Differences in descriptive characteristics between adolescent and young adult respondents and older adult respondents to the patient-reported outcomes questionnaire at diagnosis and at 1 year after diagnosis were noted (Table 1).Specifically, older adults were more likely to have metastatic disease and comorbidities and to be treated with RT only.The distribution by tumor group also differed, with older adults more frequently diagnosed with gastrointestinal and intrathoracic tumors.After adjustment, the severity of all symptoms was comparable at diagnosis between adolescents and young adults and older adults (Supplementary Tables 6 and 7, available online).At 1 year after diagnosis, adolescents and young adults had a statistically significantly greater odds of having moderate to severe depression (OR ¼ 1.7; 95% CI ¼ 1.2 to 2.2; P ¼ .001)and anxiety (OR ¼ 1.6; 95% CI ¼ 1.2 to 2.1; P ¼ .001)compared with older adults (Supplementary Tables 7 and 8, available online).Finally, when symptom trajectories were assessed, the odds of having moderate to severe symptoms over the year were statistically significantly higher among adolescents and young adults than among older adults for pain (P ¼ .003),tiredness (P ¼ .005),nausea (P < .001),depression (P < .001),anxiety (P < .001),and poor wellbeing (P < .001),after adjustment (Supplementary Tables 7-9, available online); indeed, the odds of having moderate to severe symptoms over the year was 1.4 times (pain, tiredness) to 2.4 times (anxiety) greater for adolescents and young adults than for older adults.

Discussion
To our knowledge, this is 1 of the most comprehensive studies of symptoms among adolescents and young adults with cancer to date and is 1 of only 3 studies in Canada to include an older adult comparison population (5,20).We revealed tiredness, pain, and anxiety as the most prominent symptoms in adolescents and young adults and that symptom trajectories varied substantially by tumor group.As we identified key risk factors for moderate to severe symptoms, we believe that it is possible to use our findings to educate health professionals about at-risk subpopulations of patients.Further, our results will aid in the development of interventions to improve operational care and symptom management because existing supportive care resources may not be adequately tailored to meet the needs of this young cancer population.
Our results show that tiredness, poor well-being, and anxiety were the greatest concerns among adolescent and young adult patients with cancer at diagnosis and 1 year after diagnosis; these results are consistent with other studies of adolescents and young adults that reported anxiety, fear, or worry as the top concern (20) and a high prevalence of fatigue, at 71% (21).The fact that these 3 symptoms consistently remained the greatest concerns over the year suggests that these are areas where additional supportive and individualized care can be targeted for adolescent and young adult patients.Although all symptoms improved with time, minimal changes were noted for depression (25.5% to 22.5%) and pain (27.8% to 22.5%).With respect to depression, the literature suggests that adolescent and young adult patients with cancer feel socially isolated during their oncology care because they are surrounded by substantially older patients (22,23).Further, given the relative rarity of cancer at young ages, adolescents and young adults with cancer rarely encounter other young people in their local setting with a similar diagnosis (24).Thus, age-appropriate group programs that connect adolescent and young adult patients with cancer or adolescent and young adult-specific spaces within cancer centers (25) could have a positive impact on minimizing depressive symptoms (24).Similarly, interventions seeking to address pain with attention to promotion of normal life activities may be more successful among adolescents and young adults (26).
Recognizing the importance of type of cancer on symptoms (27,28), we stratified findings by clinical tumor group.Notably, adolescent and young adult patients with sarcoma reported the worst scores across all symptoms at diagnosis.These findings correspond to the study by Maggi et al. (29), which reported high fatigue and pain for patients with sarcoma-a finding that correlated to poorer quality of life and psychological outcomes.Accordingly, our results identify a critical period at the beginning of these patients' cancer journeys that would be opportune for Table 4. Time-adjusted mixed logistic regression models a to assess the effect of time since diagnosis on the odds of having a high symptom burden (compared with a low symptom burden) among adolescents and young adult cancer survivors

ESAS-r domain
Model Time effect odds ratio (95% CI)  supportive care intervention.Although 2 adolescent and young adult nurse navigators are currently integrated into cancer care in Alberta with the purpose of helping adolescent and young adult patients with cancer understand the cancer system and available support, there may be an opportunity to prevent symptoms from reaching high levels through early recognition by front-line clinicians and the creation of automatic referrals to appropriate supportive care and rehabilitative services so that resources are integrated as soon as possible.
By 1 year after diagnosis, patients with intrathoracic and endocrine cancer reported the worst symptoms.Although our results should be interpreted with caution given our small patient population, it has been well documented that patients with lung cancer experience high levels of symptoms (30)(31)(32), which may be related to advanced stage at presentation and longer treatment duration; thus, our results are not surprising.Conversely, that we identified increased moderate to severe symptoms among patients with endocrine cancer-specifically, patients with papillary thyroid cancer (94.1% of cases)-is notable.Thyroid cancer survival rates rank among the highest of all malignancies, with this cancer often being referred to as the "good cancer" (33).This positive perception may indirectly result in a lack of interventions because the good prognosis may mistakenly be associated with a lower symptom burden (34).Our results suggest the contrary, however, with young patients with thyroid cancer reporting increasing severity across all domains, except for loss of appetite.Shifting the medical perception of thyroid cancer through education is a reasonable recommendation to ensure that symptom burdens are discussed and awareness and uptake of supportive care are increased for patients with thyroid cancer.
Important risk factors for moderate to severe symptoms include metastatic disease, female sex, treatment types received, and age at diagnosis.These results correspond to the existing literature, where patients with advanced cancer have high symptom clusters of fatigue, drowsiness, nausea, decreased appetite, and dyspnea (15).Young patients with metastatic cancer are more likely to report high levels of pain (35), and female sex is associated with high levels of psychological distress, higher burdens of nausea, and worse overall ESAS-r scores (6,15,36).Similarly, previous studies found that surgery, RT, chemotherapy, and drugs used for symptom management are associated with frequent patient reports of pain and fatigue as well as lower health-related quality of life (37,38).These identified risk factors can inform interventions to better support adolescents and young adults throughout their cancer journey.For example, it may be worth adapting the existing early palliative approach for advanced cancer care (39) to adolescents and young adult because illness comprehension and coping as well as management of symptoms could differ in this younger population facing premature mortality.As adolescent and young adult oncology is still relatively underresearched, continued investigation into the needs of adolescents and young adults is required to understand how resources, interventions, and the health-care system can be modified to improve care and outcomes.
To our knowledge, only 2 other studies have compared symptoms among adolescents and young adults with those in older or younger patients with cancer (5,20).Although our analyses did not identify differences at diagnosis, a recent study suggested higher burdens among adolescents and young adults than among older adults at diagnosis for moderate to severe anxiety (52.6% and 37.0%, respectively) (20).Our study did identify significant differences at 1 year after diagnosis and in trajectories over the year following diagnosis between the 2 groups, however.These results correspond with the existing literature, with Link et al. (5) reporting higher mean scores for anxiety, depression, and nausea among adolescents and young adults than among older adults.Although cancer disrupts life for those at all ages, the impact on career development, education, and finances is particularly worrisome for adolescents and young adults, with adolescents and young adults being 3 times more likely to identify work and school as a concern compared with older adults (5,20,40).This instability may correspond with the growing differences between adolescents and young adults and older adults in time from diagnosis in our study because cancer may be a persistent strain on their personal and professional responsibilities, whereas the impact on older adults may be more immediate.
With most reports focusing on a single cancer type, this study is among the most comprehensive because symptoms were assessed for all adolescent and young adult patients with cancer (10,21,26).Given the paucity of research on this topic, our findings substantially add to the literature because we not only describe symptoms and their trajectories over a 1-year period but also investigate important explanatory factors to identify at-risk adolescent and young adult subpopulations.Further, to contextualize whether the symptoms adolescents and young adults face are distinct from other age groups, we made comparisons with older adults.As few studies have made such a comparison to date, our findings provide novel insight into the unique needs of this young cancer population (5,20).
Despite these strengths, it is important to recognize the study's limitations.First, although considered more relevant for clinical practice (18,41), using single-item indicators for domains and dichotomizing symptom scores result in increased measurement error and loss of information, respectively.Second, we assessed the association between 8 explanatory factors and 9 symptoms, which increases the risk of type I errors.To address this concern, we used a more stringent cutoff for statistical significance (P < .01),which would reduce the number of falsepositive findings.Third, compared with the overall adolescent and young adult cancer population in Alberta, our study population included fewer individuals from the Edmonton zone as well as fewer patients with endocrine cancer and melanoma.Differences by zone can be explained by the fact that the patientreported outcomes questionnaire incrementally became electronic across the province, with the Edmonton tertiary cancer center (Cross Cancer Institute) not exclusively recording patientreported outcomes electronically until October 2019; all other cancer centers recorded patient-reported outcomes electronically during the entirety of our study.Similarly, patients with endocrine cancer and melanoma treated and followed outside the cancer center by endocrinologists and dermatologists would not be eligible to complete a patient-reported outcome questionnaire, thus explaining the differences observed.Fourth, information was not available about whether the patient-reported outcome questionnaire was completed while on or off treatment; thus, we could not assess the impact of this variable on symptom severity.Finally, although we had complete ascertainment of electronic patient-reported outcomes data for our study period, it is not mandatory to complete the patient-reported outcomes questionnaire; thus, there is potential volunteer bias.
Our study provides key insights into the unique symptom burdens that adolescent and young adult patients with cancer experience as well as risk factors that influence well-being over the year following diagnosis.These findings provide anticipatory guidance on which symptoms or subpopulations warrant increased attention and intervention-insights that can be used to educate health professionals in oncology and may lead to improved symptom control for adolescents and young adults and greater efficiency within the health-care system.Our findings can be used to counsel, educate, and empower patients so that they can advocate for the services they need.

Figure 1 .Figure 2 .
Figure 1.Proportion of adolescents and young adults and of older adults reporting a high symptom burden for each domain over the year following cancer diagnosis.

Table 1 .
Study characteristics at diagnosis and 1 year after diagnosis, by age group, with significance testing for differences by age group

Table 2 .
Summary of univariate logistic regression modeling results at diagnosis a

Table 2 .
(continued) a Reported data: top ¼ odds ratio estimate, middle ¼ 95% confidence interval, bottom ¼ P value.P values in these rows correspond to overall significance of covariates in the modeling.b Covariate is modeled as a continuous variable.c Covariate is modeling as a categorical variable, with the reference level indicated.A. Harper et al. | 7

Table 3 .
Summary of univariate logistic regression modeling results at 1 year after diagnosis a

Table 3 .
(continued) 95% confidence interval, bottom ¼ P value.P values in these rows correspond to overall significance of covariates in the modeling.
a Reported data: top ¼ odds ratio estimate, middle ¼ b Covariate is modeled as a continuous variable.c Covariate is modeling as a categorical variable, with the reference level indicated.A. Harper et al. | 9 Charlson Comorbidity Index score b þ tumor site c Models built based on univariate results presented in Supplementary TableS4(available online), where covariates with P < .01 were included in the multivariate model.ESAS-r ¼ Edmonton Symptom Assessment System. a